This is a resubmission of 1R21NS051738-01 grant application for translational research applying new technologies to amyotrophic lateral sclerosis (ALS) research. The hallmark of ALS is highly selective motor neuron degeneration. The major difficulties investigating the degeneration are limited access to the targets of investigation, motor neurons, due to reduction caused by the disease; their location in the central nervous system; variable location of pathology along the neuraxis; cell isolation; low pathogenic-to-non-pathogenic signal-to-noise ratio; and preservation of molecular quality. These can be overcome by new biotechnologies including laser-based tissue microdissection, chip-based micro-electrophoresis, linear amplification of RNA by in vitro transcription, and oligonucleotide microarray that allow isolation and collection of selected cells and profiling of their gene expression ("microgenomics"). For these biotechnologies to succeed, upfront tissue acquisition must optimally preserve RNA and deliver it to downstream biotechnologies. This is especially possible in ALS since degeneration begins focally and progresses contiguously. When it advances to the respiratory system, there are two consequences: (1) degeneration is arrested and a full spectrum of motor neuron degeneration exists around the disease epicenter-the vertical locations are knowable from clinical phenotype; and (2) RNA is preserved by an agonal state of hypercarbic respiratory failure that is without acidosis or hypoxia and it can be maintained if appropriately acquired. Microgenomics brings molecular research directly to bear on human sporadic neurodegenerative disease; keys directly on the neuronal and glial compartments of importance within the complex and heterogeneous nervous system; and performs comprehensive objective molecular exploration. While microgenomics will not distinguish primary from secondary changes of gene expression, it will create an objectively acquired library of candidate genes and pathways with which to examine old hypotheses and generate new ones; create a time-profile of the degenerative process; open new directions for further genomic and proteomic research such in situ hybridization, immunocytochemistry and knock-down or knock-in systems; and identify genes and pathways for rational therapeutic targeting by such new technologies as RNA-interference and molecular Trojan horses. [unreadable] [unreadable]